Adjuvant Treatment of Colorectal Cancer

Adjuvant Treatment of Colorectal Cancer

Approximately 106 680 new cases of colon cancer and 41 930 of rectal cancer will be diagnosed in the United States in 2006. An estimated 55 170 people will die of colorectal cancer this year.¹

Stage III colorectal carcinoma (CRC), in which the disease has already reached regional lymph nodes, is identified annually in about 200 000 persons worldwide, approximately 30 000 of whom are in the United States.² The primary management modality for such disease is surgical resection, which yields a cure rate of 50% to 60%.² By itself, however, resection of CRC is followed in 40% to 50% of cases by relapse and death from metastatic disease.² For more than 4 decades, the foundation of chemotherapy for CRC has been the fluorinated pyrimidine analogue 5-fluorouracil (5-FU), with the later addition of leucovorin (LV) as a means of improving the activity of 5-FU and rates of survival with its use.³ Adjuvant therapy for CRC was established in 1990 with the finding that postoperative chemotherapy with 5-FU and levamisole reduced mortality by 33% among patients undergoing resection of stage III disease, and subsequent studies established 5-FU/LV as the standard adjuvant regimen for stage III CRC.³ Progress in both surgery and adjuvant chemotherapy have improved the outcome of treatment for stage III CRC to the point at which the rate of 4-year survival in such disease approaches 80%,² and cure is now a possibility for some patients whose CRC might once have been considered terminal.^4,5

The first agent to be approved for addition to 5-FU/LV in adjuvant chemotherapy for CRC was oxaliplatin, a platinum-containing diaminocyclohexane molecule that acts by cross-linking DNA and thus preventing its replication and transcription.³ The US Food and Drug Administration (FDA) initially approved oxaliplatin in 2002 as part of a second- line combination regimen with 5-FU and LV for treating unresectable CRC that had progressed despite treatment with 5-FU/LV and irinotecan, which had been the first new chemotherapeutic agent to be approved for CRC since 5-FU.⁶ Subsequently, in 2004, the FDA also approved oxaliplatin for first-line treatment of CRC, on the finding that its combined use with 5-FU and LV, known as the FOLFOX regimen, provided better response rates and greater times to disease progression than did either 5-FU/LV or oxaliplatin alone in both unresectable CRC and in the adjuvant treatment of surgically resected CRC.^3,7

Strong support for FOLFOX as the standard first-line regimen for unresectable CRC also appeared in 2004 with the finding that it significantly increased the response rate, median survival time, and median time to disease progression over the combination of irinotecan with either 5-FU/LV or with oxaliplatin.⁸

Two studies, the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) and the National Surgical Adjuvant Breast and Bowel Project (NSABP) C07 trial, have been the bases for demonstrating that oxaliplatin in combination with 5-FU/LV prolongs survival over 5-FU/LV alone as an adjuvant regimen in stage II as well as in stage III CRC.^2,9-11

In the MOSAIC study, conducted at 146 centers in 20 countries, 2246 patients with stage II or III CRC who had not had any prior chemo-, radio-, or immunotherapy were treated postoperatively in 14-day cycles, in each of which LV was infused over a 2-hour period on the first day of each cycle, and 5-FU was begun in a bolus dose on the same day as LV, and was then continued in the form of a 22-hour infusion. In one arm of the study, this regimen was used alone as the basis for comparing the effect of oxaliplatin, while in the second arm of the study, oxaliplatin infused over a 2-hour period at the same time as LV was combined with the 5-FU/LV regimen.¹² At 3 years of follow-up–an interval recently suggested to effectively predict 5-year overall survival in studies of adjuvant therapy for CRC⁹–the patients in the FOLFOX-treated arm of the MOSAIC study showed a significantly higher 72.2% rate of disease-free survival than the 65.3% rate found in the 5-FU/LV-treated group.² The overall probability of survival in the FOLFOX arm of the study was also higher, at 87.7%, than the corresponding 86.6% overall survival in the 5-FU/LV arm of the study.¹²

Among toxic or adverse effects of treatment observed in the MOSAIC study, the most common serious effects in the FOLFOX-treated arm were grade 3 or 4 neutropenia, diarrhea, and vomiting, which occurred at rates of 78.9%, 56.3%, and 47.2% in this group of patients, as opposed to respective rates of 39.9%, 48.4%, and 24% in the 5-FU/LV-treated arm.¹² However, severe neutropenia accompanied by fever or infection occurred at the relatively low percentage of 1.8% among patients in the FOLFOX arm of MOSAIC, albeit at the much lower rate of 0.2% in the 5-FU/LV arm. Peripheral neuropathy occurred in 92.1% of patients in the FOLFOX arm as opposed to 15.6% in the 5-FU/LV arm, but while severe neuropathy of grade 3 was initially present in 137 patients in the FOLFOX arm, it remained in only 5 patients in a follow-up done at 1 year after treatment.¹²

A further study of oxaliplatin in adjuvant therapy for CRC is being conducted by NSABP as its seventh study of adjuvant chemotherapy for CRC in patients with stage II or III disease (NSABP C07).¹³ In this study both LV and 5-FU were given on a weekly basis for 6 weeks of an 8-week cycle that is repeated 3 times, with 5-FU given as a bolus dose rather than in the bolus-plus-infusional dose used in the FOLFOX regimen in the MOSAIC study, and with oxaliplatin given only during the first, third, and fifth weeks of each 8-week treatment cycle. At 3 years of post-treatment follow-up, the survival in the 5-FU/LV/oxaliplatin (FLOX) arm of the NSABP C07 study was the same as in the FOLFOX arm of the MOSAIC study, at 72.2%, whereas 3-year survival in the 5-FU/LV treatment arm was 65.5%.^2,11 The NSABP C07 study observed grade 3 neurosensory toxicity in 8% of patients in the FLOX arm and 1% of those in the 5-FU/LV arm.¹¹ The most recent report of the study, based on 3 years of follow-up, concluded that the addition of oxaliplatin to 5-FU/LV significantly improved survival over 5-FU/LV in the adjuvant treatment of patients with stages II and III CRC.¹¹

An issue of debate in adjuvant therapy for CRC has been whether it benefits patients with stage II as much as those with stage III disease. At 3 years of follow-up in the MOSAIC study, the hazard ratio (HR) for relapse among patients with stage II CRC was slightly greater, at 0.80, than the HR of 0.76 for patients with stage III CRC.¹² On the other hand, a recently reported 4-year follow-up of the MOSAIC study population found that patients with stage III CRC had a 25% lower risk of disease recurrence with FOLFOX than with 5-FU/LV, at 61.0% versus 69.7%, while the corresponding risk reduction for those with stage II CRC was 20%, at 85.1% versus 81.3%.¹⁰

Although an earlier pooled analysis of data from various studies failed to show a significant benefit of 5-FU/LV as adjuvant therapy in stage II CRC,¹⁴ a pooled analysis of data from NSABP studies C01 through C04 found that adjuvant therapy with 5- FU/LV provided at least the same relative benefit in stage II CRC as in stage III disease, and concluded that it should be considered the standard of care in both stage II and stage III CRC.^13,15 Moreover, the benefit of adjuvant therapy with 5-FU/LV for patients with stage II CRC has been called "consistent."²

Suggested means for refining the adjuvant treatment of CRC have included comparison studies of established adjuvant chemotherapy regimens with and without newer, targeted agents for patients with stages II and III disease, and studies for identifying specific patient features that may influence the outcome of adjuvant therapy, as opposed to the traditional use of staging and histology for this purpose.²

Bevacizumab in Colorectal Cancer.

The gains in time to disease progression and survival achieved with the addition of irinotecan and oxaliplatin to 5-FU and LV in first- and second-line treatment regimens for CRC^7,8,16-20 suggested that further gains might be achieved by the addition to such regimens of newly emergent treatment agents, some of which are targeted specifically at cell-proliferative and cell-growth factors and their receptors on the surfaces of cells, and others of which target the second-messenger systems by which these receptors induce the growth and proliferation of cells. Preclinical studies reported in 2001^21,22 and a phase 2 study reported in 2003²³ indicated that the humanized monoclonal antibody (MAb) bevacizumab could prolong survival in metastatic colorectal cancer if added to a regimen containing 5-FU, LV, and irinotecan.

The molecular target of bevacizumab is vascular endothelial growth factor (VEGF), a peptide produced both by normal and malignant cells that is thought to be the most potent factor in promoting the development of new vessels. It initiates this process of angiogenesis upon binding to its receptors in the epithelium of existing vessels, from which the new vessels branch and grow.^24,25 In order to continue to grow beyond a limited, small size, solid malignant tumors, such as CRCs, require a blood supply to provide them with oxygen and nutrition and to remove metabolic wastes. To accomplish this, these tumors generate VEGF, which promotes angiogenesis and new vessel growth, or neovascularization, of the tumors. The therapeutic rationale for bevacizumab is to prevent VEGF from binding with its receptors and initiating such vascular growth, thereby stopping tumor growth and "starving" existing tumors.

Phase 2 and 3 clinical studies have clearly shown that adding bevacizumab to 5-FU-based chemotherapy as first-line treatment for advanced CRC improves survival, progression-free survival, and the rate of response to treatment over the corresponding figures achieved with 5-FU-based chemotherapy alone.²⁶ One of 2 such studies that were instrumental to the FDA approval of bevacizumab for such combination therapy was a phase 2 trial involving 104 previously untreated patients with metastatic CRC, to whom bevacizumab was given in combination with weekly 5-FU and LV. Patients in the control arm of this study received both 5-FU and LV in doses of 500 milligrams per square meter of body surface area (mg/m²) on a single day of treatment for each of 6 weeks of an 8-week treatment cycle. In the second and third arms of the study, bevacizumab was added to the 5-FU/LV regimen at respective doses of 5 mg/kg and 10 mg/kg, each given every 2 weeks. Response rates, times to disease progression, and median survival were significantly higher in both the low- and high-dose bevacizumab arms of the study, at 40% and 24%, 9.0 and 7.2 months, and 21.5 and 16.1 months, respectively, versus 17%, 5.2 months, and 13.8 months for the corresponding measures in the 5-FU/LV control arm.²³

The second key study in the approval of bevacizumab in first-line combination chemotherapy for CRC was an international study that involved 813 patients. In this study, a regimen of 5-FU at 500 mg/m², LV at 20 mg/m², and irinotecan at 125 mg/m², all 3 of which were given once weekly for 4 weeks of a 6-week treatment cycle, was compared with the same regimen to which bevacizumab was added in a dose of 5 mg/kg given every 2 weeks.²⁷ In this study the addition of bevacizumab to 5-FU/LV/irinotecan provided striking results, increasing survival to 20.3 months versus 15.6 months with the control regimen, increasing the response rate among treated patients to 44.8% versus 34.8% and the median duration of response to 10.4 months versus 7.1 months, respectively. Hypertension, a potential safety concern with bevacizumab, occurred at a severity of grade 3 in 11.0% of patients in the bevacizumab arm as opposed to 2.3% in the control arm of the study, and was the most frequent serious adverse event in the study, but was well controlled with conventional antihypertensive therapy.²⁷ In their discussion of the study, the investigators who conducted this study pointed out that the median 4.7-month increase in survival afforded by adding bevacizumab to a regimen of 5-FU/LV/irinotecan was at least as great as any gain in survival observed in any phase 3 trial of treatment for CRC, and concluded that bevacizumab might be broadly applicable to the management of metastatic CRC.

Since its approval for use in the first-line treatment of CRC, bevacizumab has been investigated in a number of studies. An ongoing, recently reported phase 3 trial is comparing a regimen of 5-FU with LV and oxaliplatin given on day 1 of a 2-week treatment cycle, and designated FOLFOX 4, with the same regimen including bevacizumab given every 2 weeks and with this same regimen of bevacizumab as a single agent in the second-line treatment of advanced CRC.²⁸ Among 829 patients enrolled in the study through April 2003, treatment with bevacizumab added to the FOLFOX 4 regimen increased median overall survival by 17%, to 12.5 months, as compared to a survival of 10.7 months with FOLFOX 4 alone and of 10.2 months with bevacizumab alone, and increased the period of survival without disease progression to 7.4 months as opposed to respective figures of 5.5 and 3.5 months for treatment with FOLFOX 4 and bevacizumab alone.²⁸ The most serious adverse effect in this study was grade 3 sensory neuropathy, which occurred in 14.9% of patients treated with the combination of bevacizumab plus FOLFOX 4, as compared with 8.4% in the FOLFOX 4 control arm of the study and in less than 1% of patients treated with bevacizumab alone. Hypertension of grades 3/4 occurred in 6.2% of patients in the bevacizumab/ 5-FU/LV arm and 6.8% in the bevacizumab- alone arm, as opposed to a frequency of less than 1.8% in the FOLFOX 4 arm. The serious complication of bowel perforation occurred only in patients treated with bevacizumab, but at a low frequency of 1.1%. The investigators conducting the study concluded that bevacizumab in combination with FOLFOX 4 was generally well tolerated and improved the survival of patients whose CRC had progressed despite chemotherapy with a fluoropyrimidine and irinotecan.²⁸

In April 2004, the National Comprehensive Cancer Network (NCCN), in an update to its Colorectal Clinical Practice Guidelines, approved the use of bevacizumab in conjunction with 5-FU-based treatment for advanced CRC, including its use in combination regimens of 5-FU with irinotecan and oxaliplatin.²⁹ Currently, the National Cancer Institute is investigating the combination of bevacizumab plus 5-FU/LV in patients with advanced CRC that has progressed despite treatment with irinotecan- and oxaliplatin-based regimens,³⁰ while other ongoing studies have reported encouraging early data for bevacizumab in combination with oxaliplatin-containing regimens in CRC.²⁶ Trials now under way of bevacizumab in combination with standard first-line regimens for several different kinds of cancers will help determine its potential value.²⁶

Cetuximab in Colorectal Cancer.

Among the newest treatment modalities for CRC is cetuximab, an MAb directed at blocking the epithelial growth factor receptor (EGFR), a 170-kd glycoprotein belonging to the ErbB or HER family of tyrosine-kinase-containing receptors.³¹ Activation of EGFR through the binding to it of one of its endogenous ligands activates the receptor, initiating intracellular signaling processes that culminate in cell proliferation and growth, as well as other effects.

Factors contributing to the study of cetuximab in the setting of CRC have included the overexpression of EGFR by various types of tumors, including those of the colon and rectum³²; the link between the activation of EGFR and the expression of VEGF, a factor necessary for the vascularization and survival of various types of solid tumors^33,34; and the success of bevacizumab, a monoclonal antibody also directed at EGFR, when used both alone and in irinotecan- and oxaliplatin-containing chemotherapy for advanced CRC.^26-28,35

The FDA approved the use of cetuximab in 2004 as both a single agent and in combination with irinotecan for CRC that had progressed despite treatment with an irinotecan-containing regimen.³¹ Among the crucial clinical trials leading to this approval were a phase 2 study of 329 patients with irinotecan-refractory metastatic CRC in which the combination of cetuximab with irinotecan produced a significantly greater 22.9% response rate than the 10.8% rate found with irinotecan alone, in addition to producing a significantly longer time to disease progression of 4.1 versus 1.5 months, respectively.³⁵ A subsequent, open-label phase 2 study of 57 patients with metastatic CRC that had progressed despite irinotecan-based therapy reported a 9% partial response rate and a 37% rate of either minor response or stabilization of CRC with treatment with cetuximab alone.¹¹ These positive effects of cetuximab were corroborated by another study, involving 350 patients, in which cetuximab produced a 12% partial response rate in patients with metastatic CRC that had progressed despite treatment with regimens based on irinotecan, oxaliplatin, or both,³⁶ and a small phase 2 study in which cetuximab in combination with the FOLFOX 4 regimen of 5-FU, LV, and oxaliplatin produced partial responses in 81% and stable disease in 17% of previously untreated patients with metastatic CRC.³⁷ Further supporting a benefit of cetuximab in CRC are preliminary data for another phase 2 study, in which its combination with a regimen of 5-FU given by infusion, LV, and irinotecan (FOLFIRI) as first-line treatment for metastatic CRC yielded a 43% rate of partial responses to treatment and stabilized the disease in 45% of the patients.³⁸

Adverse effects of cetuximab have included a skin rash and lethargy, fatigue, or malaise.^39,40 However, although these have sometimes reached grade 3 or 4 severity,^37,39 cetuximab as a single agent has been reported to be well tolerated by most patients, and in one study, adverse effects observed with this monoclonal antibody in combination with irinotecan were reported to be of similar incidence and severity to those seen with irinotecan alone.^38,40,41

To date, cetuximab has been said to have mild to moderate activity with small gains in response rate and time to disease progression but an uncertain effect on survival in CRC that has been refractory to irinotecan.^35,42

Thus, among questions remaining in the use of cetuximab in treating CRC are whether it can increase the sensitivity to irinotecan of colorectal tumors that have proven refractory to the latter drug in a prior course of treatment. Another is whether expression of EGFR is a critical factor in predicting individual patient response to cetuximab, and whether mutations in the extracellular domain of EGFR will correlate with a response to this antibody, as recently described for the monoclonal antibody gefitinib in non-small-cell lung cancer.^35,43 Although data from the studies so far suggest that the addition of recently developed, targeted agents will expand the armamentarium of drugs for treating cancer, the advantages thus provided may be small, particularly for patients with advanced disease or cancer that has progressed despite prior treatment. In the case of cetuximab, as well as bevacizumab, further data from randomized, phase 3 trials are needed before these newer agents'roles in treating cancer can be fully established.^35,44

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